Stress is a primary contributor to the maintenance of, and relapse to smoking, and targeting stress-related relapse as a medication development strategy is a critical yet relatively unexplored area of research. Preclinical findings suggest tha noradrenergic pathways are involved in stress-induced relapse and that their manipulation may be of therapeutic benefit. Using our validated human laboratory model to examine stress- precipitated smoking lapse behavior, we have demonstrated that guanfacine, which reduces the noradrenergic tone by stimulating the alpha-2 adrenergic receptors, increased the ability to resist smoking compared to placebo, and decreased tobacco craving and ad-lib smoking following stress. This suggests a role for the noradrenergic system in stress-induced tobacco relapse. Guanfacine also reduced smoking during a subsequent brief treatment period. Based on the circuit level effects of norepinephrine on its receptors, we hypothesize that an alpha-1 adrenergic receptor antagonist should have similar effects to the alpha-2 receptor agonist. To elucidate the type of adrenergic receptors mediating the effects of norepinephrine, we collected preliminary data on stress reactivity in the laboratory with a selective alpha-1 adrenergic receptor antagonist, prazosin, supporting a role for alpha-1 adrenergic receptors in stress-induced tobacco relapse. However, prazosin is short-acting and must be administered three times daily, reducing the likelihood of medication compliance and limiting its potential effectiveness. Doxazosin (Cardura(R), Pfizer, marketed for hypertension and benign prostatic hyperplasia) is an alpha-1 agent similar to prazosin, but has a longer half-life (22hrs) improving the likely compliance with and effectiveness of this medication. Thus, the primary aim of this Explorarory/Developmental R21 application is to conduct an initial Phase II double-blind, between-subject, placebo-controlled pilot study to evaluate whether an alpha-1 adrenergic antagonist, doxasozin (0mg/day, 4mg/day, 8mg/day) counteracts stress-induced effects on smoking behavior in the laboratory (i.e., increases the ability to resist smoking, reduces ad-lib smoking) and improves clinical outcomes during a subsequent brief treatment phase (i.e., reductions in smoking behavior). We will also examine potential mechanisms underlying stress-precipitated smoking lapse (e.g., craving, mood, cardiovascular reactivity, HPA axis reactivity, catecholamines) and explore additional mechanisms hypothesized to underlie noradrenergic effects on smoking behavior (e.g., reductions in withdrawal symptoms and smoking-related reinforcement). To our knowledge, this will be the first investigation examining the therapeutic potential and associated mechanisms of a selective alpha-1 adrenergic antagonist, doxazosin for the treatment of tobacco dependence. Positive findings will validate our hypothesis on the role of norephinephrine receptor subtypes in stress reactivity, and will provide key information necessary to expand this investigation to a clinical trial. PUBLIC HEALTH RELEVANCE: Stress is a primary contributor to the maintenance of, and relapse to smoking, and targeting stress-related relapse as a medication development strategy is a critical yet relatively unexplored area of research. Preclinical findings suggest that noradrenergic pathways are involved in stress-induced relapse and that their manipulation may be of therapeutic benefit. The primary aim of this Exploratory/Developmental R21 application is to conduct an initial Phase II double-blind, between-subject, placebo-controlled pilot study to evaluate whether an alpha-1 adrenergic antagonist, doxasozin (0mg/day, 4mg/day, 8mg/day) counteracts stress- induced effects on smoking behavior in the laboratory (i.e., increases the ability to resist smoking, reduces ad- lib smoking) and improves clinical outcomes during a subsequent brief treatment phase (i.e., reductions in smoking behavior).